ABSTRACT / PROJECT SUMMARY Shock wave lithotripsy (SWL) is a widely used noninvasive procedure to break symptomatic kidney stones, with more than 300,000 treatments annually in the U.S. Though SWL is appealing as a noninvasive treatment option, repeat treatments and/or ancillary invasive procedures are commonly required to render the patient entirely stone free. Indeed, SWL is successful in only about 50% of cases. In addition to relatively low success rates, SWL can cause injury to the kidney and surrounding tissues that can have serious consequences. In Project 2, we build on understanding of the mechanisms of stone fragmentation in SWL to design a related, but fundamentally distinct, noninvasive treatment to reliably and safely break stones into uniformly small fragments that are passable and clinically insignificant. This new burst wave lithotripsy (BWL) approach delivers several- cycle bursts of sub-megahertz ultrasound without shocks, using pressure amplitudes significantly lower than those in SWL. Preliminary studies with a 170 kHz transducer demonstrate that BWL breaks both artificial and natural stones (calcium oxalate monohydrate, uric acid, struvite, cystine) into more uniformly small fragments than SWL, faster than clinical SWL. Parallel studies at higher frequencies suggest that fragment sizes are controlled by the ultrasound frequency. Beyond stone fragmentation, initial in vivo experiments indicate that stones can be broken using BWL parameters that induce almost no injury in pig kidneys. The overarching objective of this effort is to advance BWL toward clinical use. Relevant parameters for BWL treatment include the ultrasound frequency and amplitude, the number of acoustic cycles in each ultrasound burst, and the rate at which bursts are delivered. The first three Aims of this proposal seek to design effective and safe BWL treatment protocols with these parameters by (1) testing for optimal conditions to efficiently break stones into easily passable (<1 mm) fragments; (2) identifying and modeling mechanisms for stone comminution and tissue injury to improve the procedure by direct exploration of the parameter space; and (3) evaluating the injury potential of BWL treatments with in vivo testing on the pig model. With design inputs from these three Aims, the goal of Aim (4) is to develop and test a pre-clinical BWL prototype. The proposed studies are designed synergistically with both the Project 1 studies on ultrasound-based technologies for stone imaging and manipulation and the Project 3 studies on acoustic cavitation injury. The work will benefit public health by providing a novel strategy for non-invasive extracorporeal lithotripsy (without shock waves) that will lead to faster, safer, more effective clinical treatments with improved outcomes for stone patients.